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Article
Nature Medicine 11, 175 - 182 (2005)
Published online: 30 January 2005 | doi:10.1038/nm1187
Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice
Tohru Uchida1,5, Takehiro Nakamura1,5, Naoko Hashimoto1, Tomokazu Matsuda1, Ko Kotani1, Hiroshi Sakaue1, Yoshiaki Kido1, Yoshitake Hayashi2, Keiichi I Nakayama3, Morris F White4 & Masato Kasuga1
Abstract
The protein p27Kip1 regulates cell cycle progression in mammals by inhibiting the activity of cyclin-dependent kinases (CDKs). Here we show that p27Kip1 progressively accumulates in the nucleus of pancreatic beta cells in mice that lack either insulin receptor substrate 2 (Irs2-/-) or the long form of the leptin receptor (Lepr-/- or db/db). Deletion of the gene encoding p27Kip1 (Cdkn1b) ameliorated hyperglycemia in these animal models of type 2 diabetes mellitus by increasing islet mass and maintaining compensatory hyperinsulinemia, effects that were attributable predominantly to stimulation of pancreatic beta-cell proliferation. Thus, p27Kip1 contributes to beta-cell failure during the development of type 2 diabetes in Irs2-/- and Lepr-/- mice and represents a potential new target for the treatment of this condition.
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